Peripheral neuropathic pain is now the most common neurological complication in HIV-infected individuals undergoing cART. However, it is still under-studied because appropriate experimental animal models have not yet been developed. Recent data from us and others show that distal symmetric polyneuropathy (DSP) develops along with murine acquired immunodeficiency syndrome (MAIDS) following infection with the LP- BM5 retrovirus mixture. For centuries, derivatives of Cannabis sativa have been used as analgesics, and a link between cannabinoid receptor 2 (CB2R) and peripheral neuropathy has been established in animal models using nerve transection, chemical-induced pain, and various other stimuli. Diverse types of peripheral neuropathic pain respond differently to standard drug intervention and nothing is currently known regarding the effects of inflammatory modulation through CB2Rs in the context of peripheral neuropathy due to chronic retroviral infection. The experiments proposed in this application will fill this gap in knowledge. The central hypothesis to be tested is that modulation using CB2R agonists can control chronic immune activation-induced neuropathic pain seen during retroviral infection. The studies will first examine the extent of immune activation within the lumbar spinal cord (LSC) and dorsal root ganglia (DRG) in MAIDS animals with peripheral neuropathy. This will be achieved by assessing CD4+ T-cell and macrophage infiltration into the LSC and DRG, as well as activation of resident glia. We will also determine how CD4+ regulatory T-cell (Treg) dysregulation contributes to DSP. Studies will go on to determine the role of endogenous CB2Rs in controlling chronic inflammation-induced neuropathic pain. This will be achieved by giving MAIDS to CB2R knockout mice and assessing infection-induced peripheral neuropathy via mechanical sensitivity using MouseMet electronic von Frey and intra-epidermal nerve fiber loss in hind paw tissue biopsies. We will also assess its associated glial activation and inflammation-induced neurotoxicity. In the final set of experiments, we will determine whether exogenous synthetic CB2R agonists inhibit chronic immune activation, neuropathic pain, and subsequent neuronal damage. This will be achieved by treating wild-type MAIDS animals with exogenous synthetic CB2R agonists to determine if they inhibit damage within the LSC and DRG. A number of studies investigating the mechanisms leading to peripheral neuropathy have been carried out in vitro, but ultimately these in vitro findings require further validation using in vivo models. There are no FDA-approved pharmacologic agents available which are specifically designed for treatment of chronic HIV-associated neuropathy. Analgesics currently used target neurons, but are only modestly effective for chronic pain. Five decades of research focused on neurons has not brought about a real solution to neuropathic pain. New approaches which lead to development of more specific and effective analgesics are desperately needed; and immunomodulation through the CB2R system is clearly a promising strategy.